30mg and 50mg pre-filled pen (Eperzan ®) SMC No. (1024/15) GlaxoSmithKline

09 January 2015 (Issued December 2015)

The Scottish Medicines Consortium (SMC) has completed its assessment of the above product and advises NHS Boards and Area Drug and Therapeutic Committees (ADTCs) on its use in Scotland. The advice is summarised as follows:

ADVICE : following a full submission

albiglutide (Eperzan ®) is accepted for restricted use within NHS Scotland.

Indication under review : Treatment of type 2 mellitus in adults to improve glycaemic control in combination with other -lowering medicinal products including basal , when these, together with diet and exercise, do not provide adequate glycaemic control.

SMC restriction: an alternative once weekly -like -1 (GLP-1) agonist for use in combination with oral anti-diabetic agents as a third-line pre-insulin treatment option.

As add-on combination therapy, albiglutide was superior to placebo and to some oral comparators for glycaemic control. It was inferior to an alternative GLP-1 agonist and non- inferior to insulin.

This SMC advice takes account of the benefits of a Patient Access Scheme (PAS) that improves the cost-effectiveness of albiglutide. This advice is contingent upon the continuing availability of the PAS in NHS Scotland or a list price that is equivalent or lower.

Albiglutide is also indicated for adults with mellitus to improve glycaemic control as monotherapy when diet and exercise alone does not provide adequate glycaemic control in patients for whom use of is considered inappropriate due to contraindications or intolerance. SMC has not reviewed albiglutide in this indication and cannot recommend its use within NHS Scotland.

Overleaf is the detailed advice on this product.

Chairman, Scottish Medicines Consortium

Published 11 January 2016 1

Indication Treatment of type 2 diabetes mellitus in adults to improve glycaemic control as: • Monotherapy: When diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to contraindications or intolerance. • Add-on combination therapy: In combination with other glucose-lowering medicinal products including basal insulin, when these, together with diet and exercise, do not provide adequate glycaemic control.

Dosing Information 30mg subcutaneously once weekly. Dose may be increased to 50mg once weekly based on individual glycaemic response. Albiglutide may be administered at any time of day without regard to meals. It should be administered on the same day each week.

When albiglutide is added to existing metformin therapy, the current metformin dose can be continued unchanged. It may be necessary to reduce the dose of concomitantly administered insulin secretagogues (such as sulphonylureas) or insulin to reduce the risk of hypoglycaemia when starting albiglutide.

Product availability date December 2015

Summary of evidence on comparative efficacy

Albiglutide is a glucagon-like peptide-1 (GLP-1) agonist indicated for type 2 diabetes as monotherapy and in combination with other glucose-lowering medicines 1. The submitting company has requested that the Scottish Medicines Consortium (SMC) considers albiglutide when positioned for use as the first injectable anti-diabetic medicine for patients with inadequate glycaemic control on oral anti-diabetic drugs (OADs), who are eligible for a GLP-1 agonist, and in whom once weekly administration is preferred.

Eight phase III studies recruited adults with type 2 diabetes mellitus not controlled, defined as glycosylated haemoglobin (HbA1c) ≥7% (but not exceeding 10%; 10.5% for HARMONY-6), on their anti-diabetic regimen, which varied across the studies as detailed in the table below. Only patients with renal impairment, defined as estimated glomerular filtration (eGFR) ≥15 and <90ml/min/1.73m 2 were permitted to enter HARMONY-8. Randomisation was stratified by prior myocardial infarction (MI) (yes or no), HbA1c (<8.0% or ≥8.0%, except in HARMONY-1, no stratification, and HARMONY-6, <8.5% or ≥8.5%), age (<65 or ≥65years, except in HARMONY- 6), by background OAD therapy in HARMONY-1, -4 and -6 studies and by renal impairment (mild, moderate or severe) in HARMONY-8. Patients received albiglutide subcutaneous (SC) injection weekly or comparators as detailed in the table below. The primary endpoint was change from baseline in HbA1c at 26 weeks in studies HARMONY-6 and -8; at 32 weeks in HARMONY-7, at 104 weeks in HARMONY-3, and at 52 weeks in the four other studies. This was compared between treatment groups by an analysis of covariance (ANCOVA) with main effects for treatment group, region, previous MI and age category, and with baseline HbA1c as continuous covariate. The primary analyses were conducted in the intention to treat (ITT)

2 population, which comprised all randomised patients who received at least one dose of study drug and had a baseline and at least one post-baseline HbA1c measurement, with last observation carried forward (LOCF) for missing data and data after rescue medication. Observed case analyses were also conducted to support the primary analyses. 2-15

For the primary outcomes, albiglutide significantly reduced HbA1c compared with placebo in HARMONY-1, -2, -3, and -5. Albiglutide was superior to 2 to 4mg daily and 100mg daily in HARMONY-3 and superior to sitagliptin 25mg to 100mg in HARMONY-8. Albiglutide was inferior to 30 to 45mg daily in HARMONY-5 and inferior to 1.8mg daily in HARMONY-7. In HARMONY-4, which had a non-inferiority margin of 0.3%, albiglutide demonstrated non-inferiority to , and in HARMONY-6, which had a non-inferiority margin of 0.4%, albiglutide was non-inferior to pre-prandial . These data are shown in the table along with the secondary outcome, change from baseline in body weight. The European Medicines Agency (EMA) considered albiglutide to be weight neutral. 2-15

Table: Adjusted mean changes from baseline in HbA1c and body weight with differences between albiglutide and comparators at primary endpoint. 2-15 HbA1c (%) Body weight (kg) Mean Difference* Mean Difference* Monotherapy (HARMONY -2 at 52 weeks): Albiglutide 30mg weekly -0.70 -0.83 (-1.11; -0.58) -0.39 0.27 (-0.091; 1.46) Albiglutide 50mg weekly -0.89 -1.04 (-1.31; -0.77) -0.86 -0.20 (-1.40; 1.01) Placebo 0.15 - -0.66 - In combination with metformin (HARMONY -3 at 104 weeks) Albiglutide 30 to 50mg weekly -0.63 - -1.21 - Glimepiride 2 to 4mg daily -0.36 -0.27 (-0.45; -0.09) 1.17 -2.37 (-3.03; -1.71) Sitagliptin 100mg daily -0.28 -0.35 (-0.53; -0.17) -0.86 -0.35 (-1.01; 0.31) Placebo 0.27 -0.91 (-1.16; -0.65) -1.00 -0.20 (-1.14; 0.73) In combination with metformin ± sulphonylurea (HARMONY -5 at 52 weeks) Albiglutide 30 to 50mg weekly -0.55 - -0.42 - Pioglitazone 30 to 45mg daily -0.80 0.25 (0.10; 0.40) 4.43 -4.85 (-5.51; -4.20) Placebo 0.33 -0.87 (-1.07; -0.68) -0.40 -0.03 (-0.88; 0.82) In combination with metformin ± sulphonylurea (HARMONY -4 at 52 weeks) Albiglutide 30 to 50mg weekly -0.67 - -1.05 Insulin glargine at night -0.79 0.11 (-0.04; 0.27) 1.56 -2.61 (-3.20; -2.02) In combination with pioglitazone ± metformin (HARMONY -1 at 52 weeks) Albiglutide 30 to 50mg weekly -0.81 - 0.28 - Placebo -0.05 -0.75 (-0.95; -0.56) 0.45 -0.18 (-1.15; 0.79) In combination with basal insulin (HARMONY -6 at 26 wee ks) Albiglutide 30 to 50mg weekly -0.82 -0.73 Insulin lispro pre-prandial -0.66 -0.16 (-0.32; 0.00) 0.81 -1.54 (-2.09; -1.00)

In combination with various oral anti -diabetics (HARMONY -7 at 32 weeks) Albiglutide 50mg weekly -0.78 -0.64 Liraglutide 1.8mg daily -0.99 0.21 (0.08; 0.34) -2.19 1.55 (1.05; 2.06)

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In patients with renal impairment (HARMONY -8 at 26 weeks) Albiglutide 30 to 50mg weekly -0.83 -0.79 Sitagliptin 25 to 100mg daily -0.52 -0.32 (-0.49; -0.15) -0.19 -0.60 (-1.14; -0.06) Albiglutide 30 to 50mg weekly; pioglitazone 30mg to 45mg daily = patients commenced on the lower doses and the dose could be increased to the higher dose if required. Sitagliptin 25mg to 100mg = dose determined by degree of renal impairment.

Summary of evi dence on comparative safety

In general, the adverse event profile of albiglutide is similar to other GLP-1 agonists, with gastro-intestinal events commonly reported. In the comparison to liraglutide (HARMONY-7), nausea was less frequently reported by those receiving albiglutide compared to liraglutide: 10% versus 29%, respectively. Injection-site reactions (ISR) are also reported with GLP-1 agonists and in HARMONY-7 these were significantly more frequent in the albiglutide group compared with liraglutide: 6.9% versus 1.2%. In analysis that included the term ISR and other related terms, albiglutide was associated with higher frequencies of events than other injected therapies: 13% versus 5.4% for albiglutide compared to liraglutide; 9.5% versus 5.3% for albiglutide versus insulin lispro; and 17% versus 10% for albiglutide versus insulin glargine. In the integrated safety database, the main adverse event that led to treatment discontinuation in the albiglutide group, which occurred at a higher rate than with placebo, was ISR. In this database, the incidence of pneumonia was significantly higher with albiglutide versus all comparators: 1.75% versus 0.79%; this imbalance was noted across all individual studies. A mechanism for this has not been identified. 2

Rates of hypoglycaemia when albiglutide was used as monotherapy were low. However, these increased when it was used in combination with sulphonylurea or insulin. Rare, but more serious, adverse events associated with GLP-1 agonists include intestinal obstruction and acute pancreatitis. Pancreatic and thyroid cancers are also noted as potential safety issues and monitored in pharmacovigilance activities. 2

In an integrated analysis of data from the eight phase III studies, atrial fibrillation or flutter occurred more frequently in the albiglutide group than in the comparators groups: 1.3% versus 0.5%. A case review did not provide an explanation for this. Albiglutide is also associated with a dose-dependent increase in heart rate. Transient ischaemic attack (TIA) occurred in a larger proportion of patients given albiglutide than all comparators: 0.6% versus 0.2%, respectively. Cerebrovascular accident (CVA) occurred in 0.33% and 0.18% of patients in the respective groups. However, atrial fibrillation prior to TIA or CVA was noted for only 2 of the 20 reported cases. The incidence of first major adverse cardiovascular event (MACE) was similar in the albiglutide group versus the all comparators group, 1.2 versus 1.1 per 100 patient-years, respectively. 2

Su mmary of clinical effectiveness issues

Albiglutide is the fourth GLP-1 agonist to be licensed in the UK for the treatment of diabetes and the second in a once-weekly formulation (after extended release [ER]). Medicines in this class mimic the effects of endogenous GLP-1, which stimulates glucose-dependent insulin secretion, thereby increasing glucose uptake in tissues, and suppresses glucagon secretion,

4 thereby reducing hepatic glucose output. GLP-1 also suppresses appetite, delays gastric emptying and reduces intestinal motility, thereby decreasing the rate of glucose absorption. In patients with type 2 diabetes, the postprandial rise in endogenous GLP-1 is reduced or absent. GLP-1 agonists can supplement or replace this deficiency. 2 The submitting company has requested that SMC considers albiglutide when positioned for use as the first injectable anti- diabetic medicine for patients with type 2 diabetes uncontrolled on OADs, who are eligible for a GLP-1 agonist and for whom once-weekly administration is preferable.

In the phase III HARMONY study programme, the primary outcome was change from baseline in HbA1c. 2 This is an established measure of blood glucose control over the preceding two to three months. In the UK, HbA1c results are expressed in mmol/mol rather than as a percentage. The equivalent of the HbA1c targets of 6.5% and 7.5% are 48mmol/mol and 58mmol/mol.

In the phase III HARMONY studies, albiglutide as monotherapy and add-on to OADs significantly reduced HbA1c compared with placebo. The EMA notes that the placebo-corrected reduction in most studies was approximately 0.8% to 1.0%. In direct comparative studies, albiglutide was superior to glimepiride and sitagliptin. However, it was inferior to pioglitazone and liraglutide. It was non-inferior to insulin glargine, using a margin of 0.3%, and to insulin lispro, using a margin of 0.4%. 2,3 Within the positioning proposed by the company, as first injectable therapy in patients who are failing to respond to OADs, the most useful data derive from HARMONY-7 and HARMONY-4. In HARMONY-7, albiglutide 50mg weekly was inferior to liraglutide 1.8mg daily in patients with diabetes that was uncontrolled on various OADs, which comprised dual therapy (mostly metformin and sulphonylurea) for 51% of patients, triple therapy for 7.4% and monotherapy for 41% (mostly metformin, 36%). In HARMONY-4, albiglutide 30 to 50mg weekly was non-inferior to insulin glargine (a basal insulin) in patients with diabetes that was uncontrolled on metformin ± sulphonylurea, with 82% of patients on metformin plus sulphonylurea at baseline.

In the HARMONY programme, the percentage of missing data for the primary endpoint increased as time of the endpoint increased and was larger for placebo groups. In the primary analysis, missing data were handled using LOCF, which may not be the most appropriate method. Within active groups, the percentage of missing data for HbA1c when this was primarily assessed at week 26 or week 32, was 17% to 31%; at week 52, was 32% to 42% (and 58% to 70% for placebo); and at week 104, was 46% to 55% (and 76% for placebo). The large amount of missing data may undermine reliability and confidence in the results. 4 However, the US and European regulatory authorities noted that sensitivity analyses performed to address this were consistent with primary analyses. 2,3

Three studies (HARMONY-4, -6 and -7) had an open-label design and this may compromise data for subjective outcomes, such as adverse events. It may also affect discontinuation rates.

Within the licensed indication, possible comparators would be all other anti-diabetic medicines. In accordance with SIGN guidance, it is likely to be used as a third-line pre-insulin treatment option in patients failing on OADs, and in this context, comparators would include other GLP-1 agonists (liraglutide, exenatide, exenatide ER and ) and basal (human isophane insulin, , insulin detemir and insulin glargine). However, the submitting company has requested that SMC considers albiglutide when positioned for use as the first injectable anti-diabetic medicine for patients with diabetes not controlled on OADs, who are eligible for a GLP-1 agonist and in whom once weekly administration is preferred. In this context the only relevant comparator is exenatide ER.

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A Bucher indirect comparison of the effects of albiglutide 50mg weekly and exenatide ER 2mg weekly on HbA1c was performed. This supports an assumption of equivalence between these medicines, which underpins the cost-minimisation economic analysis. The comparison included data from the HARMONY-7 study 2-4,13,14 and the DURATION-6 study, 16 which both included a liraglutide 1.8mg daily treatment arm. The outcome included in the comparison was change in HbA1c from baseline to week 32 and week 26 in the respective studies. It concluded that albiglutide and exenatide XR have comparable efficacy in reducing HbA1c. Weaknesses of the comparison include differences across the studies in statistical analyses, especially with respect to handling missing data and differences in the treatment effect observed in the common comparator arm. Also, other outcomes, which could be potentially relevant have not been formally assessed in the comparison e.g. change in body weight and rates of adverse events such as hypoglycaemia and injection-site reactions. There is also the possible omission of other studies that could have informed the comparison of relative treatment effects of these medicines.

In comparison to exenatide ER, the licensed indications for albiglutide are broader to include use in combination with insulin and as monotherapy. Unlike exenatide ER, albiglutide is licensed for use without dose adjustments in patients with moderate renal impairment. It is also available in an alternative pen injection device which may benefit some patients.

Summary of comparative health economic evidence

The company submitted a cost-minimisation analysis comparing albiglutide with exenatide ER for the selective positioning as a third-line, first injectable medicine for patients with type 2 diabetes who are uncontrolled on OADs, and for whom once-weekly administration is preferable. Based on SMC clinical experts’ responses the comparator seems appropriate. A one-year time horizon was used and the analysis was carried out from an NHS Scotland perspective. The sensitivity analysis explored three and five year time horizons.

No direct clinical studies comparing albiglutide and exenatide ER were identified by the submitting company and, therefore, a Bucher indirect comparison of albiglutide and exenatide ER, as described above, was conducted to support the cost-minimisation analysis. The results of the indirect comparison suggested that comparable efficacy had been demonstrated between albiglutide and exenatide ER.

The only costs included by the submitting company were drug acquisition costs per patient per year.

In the first year, the base case results showed estimated savings associated with albiglutide of £31 per patient assuming all patients receive the 50mg dose.

A confidential Patient Access Scheme (PAS) was submitted by the company and assessed by the Patient Access Scheme Assessment Group (PASAG) as acceptable for implementation in NHS Scotland. Under the PAS, a simple discount was offered which reduced the list price of albiglutide 30mg and 50mg. With the PAS, albiglutide remained a cost-effective treatment option.

Sensitivity analysis was conducted varying the proportion of patients on albiglutide 30mg and 50mg using the ratio of 30mg and 50mg dose from clinical trials which showed that 40% of

6 patients may require the 30mg dose and 60% require 50mg. Using these proportions did not alter the conclusion of the analysis.

The analysis shows albiglutide has comparable efficacy to exenatide ER and, based on this assumption, it is a cost-effective treatment option. Therefore, the economic case has been demonstrated.

Summary of patient and public involvement

A Patient Group Submission was not made.

Additional information: guidelines and protocols

The Scottish Intercollegiate Guidelines Network (SIGN) published updated guidance on the Management of diabetes in March 2010. The treatment algorithm notes several options for third- line treatment of type 2 diabetes mellitus to be added in combination with metformin and/or sulphonylurea; additional oral anti-diabetic drugs, pioglitazone or DPP-4 inhibitors; or injections of GLP-1 agonists or commencement of insulin. GLP-1 agonists are recommended for patients with a BMI >30kg/m 2 who wish to lose weight and have had diabetes for less than 10 years. Treatment should be continued if an individualised target is reached or the HbA1c falls at least 0.5% in 3 to 6 months. 17

The National Institute for Health and Care Excellence (NICE) published Clinical Guideline 87; Management of type 2 diabetes in May 2009. The guideline advised on cost effective use of exenatide as a third-line agent. 18

The American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) published a position statement “Management of Hyperglycaemia in type 2 diabetes: a patient-centred approach” in June 2012. A patient-centred approach is advocated with individualisation of treatment. Beyond lifestyle advice and initial drug therapy with metformin a number of treatment options are recommended with no specific preference: choice is based on patient and drug characteristics.19

Additional information: comparators

The relevant comparator given the company’s positioning is the GLP-1 agonist, exenatide ER.

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Cost of rel evant comparators

Drug Dose Regimen Cost per year (£) Albiglutide 30 to 50 micrograms SC once weekly 923 Exenatide ER 2 milligrams SC once weekly 954 Doses are for general comparison and do not imply therapeutic equivalence. Exenatide ER cost from eVadis 03 October 2014. Albiglutide cost is from the company’s submission. SC = subcutaneous injection.

Additional information: budget impact

The submitting company estimated there to be 563 patients eligible for treatment with albiglutide in year 1 in the proposed positioning, rising to 721 in year 5; this is an estimated uptake rate of 10% in year 1 and 52% in year 5.

Without the PAS, the gross impact on the medicines budget was estimated to be £44k in year 1 and £334k in year 5. As other drugs were assumed to be displaced, the net medicines budget impact was estimated to be savings of £1k in year 1 and £11k in year 5.

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References

The undernoted references were supplied with the submission. Those shaded in grey are additional to those supplied with the submission.

1. GlaxoSmithKline. Albiglutide summary of product characteristics 2. European Medicines Agency. Albiglutide European public assessment report 3. US Food and Drug Administration. Albiglutide medical review 4. US Food and Drug Administration. Albiglutide statistical review 5. GlaxoSmithKline. Clinical study report for GLP112755 (HARMONY-1) 6. GlaxoSmithKline. Clinical study report for GLP112756 (HARMONY-2) 7. GlaxoSmithKline. Clinical study report for GLP112753 (HARMONY-3) 8. Ahern B, Johnson SL, Stewart M et al. HARMONY 3: 104-Week Randomized, Double-Blind, Placebo- and Active-Controlled Trial Assessing the Efficacy and Safety of Albiglutide Compared With Placebo, Sitagliptin, and Glimepiride in Patients With Type 2 Diabetes Taking Metformin. Diabetes Care 2014; 37: 2141-8. 9. GlaxoSmithKline. Clinical study report for GLP112754 (HARMONY-4) 10. GlaxoSmithKline. Clinical study report for GLP112757 (HARMONY-5) 11. GlaxoSmithKline. Clinical study report for GLP108486 (HARMONY-6) 12. Rosenstock J, Fonseca VA, Gross JL et al. Advancing Basal Insulin Replacement in Type 2 Diabetes Inadequately Controlled With Insulin Glargine Plus Oral Agents: A Comparison of Adding Albiglutide, a Weekly GLP-1 Receptor Agonist, Versus Thrice-Daily Prandial Insulin Lispro. Diabetes Care 2014; 37: 2317–25. 13. GlaxoSmithKline. Clinical study report for GLP114179 (HARMONY-7) 14. Prately RE, Nauck MA, Barnett AH et al. Once weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs (HARMONY-7): a randomised, open-label, multicentre, noninferiority phase 3 study. Lancet Diabetes Endocrinol 2014; 2: 289-97 15. GlaxoSmithKline. Clinical study report for GLP114130 (HARMONY-8) 16. Buse JB, Nauck M, Forst T et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet 2013; 381: 117-24 17. Scottish Intercollegiate Guidelines Network (SIGN). Publication number 116; Management of diabetes, March 2010 18. National Institute for Health and Care Excellence (NICE). Clinical guideline number 87; Type 2 diabetes, May 2009. 19. Inzucchi SE. Management of hyperglycaemia in type 2 diabetes: a patient centred approach. Diabetes Care 2012; 35: 1364-79

This assessment is based on data submitted by the applicant company up to and including 3 December 2015.

Drug prices are those available at the time the papers were issued to SMC for consideration. SMC is aware that for some hospital-only products national or local contracts may be in place for comparator products that can significantly reduce the acquisition cost to Health Boards. These contract prices are commercial in confidence and cannot be put in the public domain, including via the SMC Detailed Advice Document. Area Drug and Therapeutics Committees and NHS Boards are therefore asked to consider contract pricing when reviewing advice on medicines accepted by SMC.

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Patient access schemes: A patient access scheme is a scheme proposed by a pharmaceutical company in order to improve the cost-effectiveness of a drug and enable patients to receive access to cost-effective innovative medicines. A Patient Access Scheme Assessment Group (PASAG, established under the auspices of NHS National Services Scotland reviews and advises NHS Scotland on the feasibility of proposed schemes for implementation. The PASAG operates separately from SMC in order to maintain the integrity and independence of the assessment process of the SMC. When SMC accepts a medicine for use in NHS Scotland on the basis of a patient access scheme that has been considered feasible by PASAG, a set of guidance notes on the operation of the scheme will be circulated to Area Drug and Therapeutics Committees and NHS Boards prior to publication of SMC advice.

Advice context:

No part of this advice may be used without the whole of the advice being quoted in full.

This advice represents the view of the Scottish Medicines Consortium and was arrived at after careful consideration and evaluation of the available evidence. It is provided to inform the considerations of Area Drug & Therapeutics Committees and NHS Boards in Scotland in determining medicines for local use or local formulary inclusion. This advice does not override the individual responsibility of health professionals to make decisions in the exercise of their clinical judgement in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.

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